Chapter 60 / Disorders of Thought and Volition in Schizophrenia 1491
Figure 60–1 The lifetime risk of schizo-
phrenia increases as a function of
genetic relatedness to a person with
schizophrenia. The risk of schizophre-
nia rises with genetic relatedness to an
affected individual and, therefore, with
increased sharing of DNA sequences.
However, the pattern of segregation in
families does not follow simple Mendelian
ratios; rather, inheritance reflects genetic
complexity. In addition, risk varies within
categories of relatedness (first- and sec-
ond-degree relatives), suggesting a role for
unshared developmental or environmental
effects. (Reproduced, with permission,
from Gottesman 1991.)
predictive of schizophrenia than the rate of schizo-
phrenia in the adoptive family.
Kety and his colleagues also observed that some
of the biological relatives of adoptees with schizo-
phrenia exhibited milder symptoms related to schiz-
ophrenia, such as social isolation, suspiciousness,
eccentric beliefs, and magical thinking, but not frank
hallucinations or delusions. Since Kety’s time, it has
been observed that such relatives may also exhibit
cognitive impairments that are intermediate between
unaffected individuals and those with schizophrenia.
They also may exhibit thinning of the cerebral cortex
observed by magnetic resonance imaging (MRI) that
is also intermediate between healthy individuals and
those with schizophrenia. (Cortical thinning in schizo-
phrenia is discussed below.) Such individuals are now
diagnosed with schizotypal disorder, which appears
to be the milder end of the schizophrenia spectrum of
psychotic disorders. The severity and nature of symp-
toms appear to be influenced by the individual’s over-
all burden of risk-associated genetic variants as well as
exposure to environmental risk factors.
Irving Gottesman’s studies of extended pedigrees
of Danish patients with schizophrenia supported the
importance of genes. Gottesman noted the correlations
between the risk of schizophrenia in relatives and the
degree to which they shared DNA sequences with an
affected person. He found a greater lifetime risk of
schizophrenia among first-degree relatives (includ-
ing parents, siblings, and children, who share 50% of
DNA sequences with the patient) than among second-
degree relatives (including aunts, uncles, nieces,
nephews, and grandchildren, who share 25% of their
DNA sequences). Even third-degree relatives (who
share only 12.5% of the patient’s DNA sequences)
were at higher risk for schizophrenia than the approxi-
mately 1% of the general population at risk for this dis-
ease (Figure 60–1).
Based on the differences in levels of risk Gottesman
measured in these pedigrees, he recognized that schiz-
ophrenia risk was not transmitted within families as
Mendelian dominant or recessive traits (ie, it was not
caused by a single genetic locus). He predicted cor-
rectly that schizophrenia is a polygenic trait, involving
a large number of loci throughout the human genome.
This genetic architecture underlies many human pheno-
types, including disease phenotypes, and may involve
many hundreds of loci within the genome. In polygenic
traits, variants at each disease-associated locus contrib-
ute small, additive effects to the phenotype. Genetic risk
variants act together with environmental factors to pro-
duce the schizophrenia phenotype.
In 2014, a large global consortium reported on a
genome-wide association study of more than 35,000
individuals with schizophrenia. The study identi-
fied 108 genome-wide significant loci associated
with schizophrenia that were distributed across the
genome. The research continues, and the number of
known loci is already greater than 250. Each of these
loci represents a segment of DNA identified by a single
10 20 30 40
发展为精神分裂症的终生风险 (%)
500
无(普通人群)
与精神分裂症患者的关系
基因共享
12.5%
(三级亲属)
25%
(二级亲属)
50%
(直系亲属)
100%
表兄弟
叔叔/阿姨
侄子/侄女
孙子
半同胞
父母
同胞兄弟姐妹
子女
异卵双生
同卵双生
2%
1%
2%
4%
5%
6%
6%
9%
13%
17%